Deposition of islet amyloid pancreatic polypeptide (IAPP) in the islets of Langerhans is the characteristic feature of human type 2 diabetic pancreas but represents the final stage of a process started long before. Recent evidence suggests that [unreadable]-cell toxicity of amyloidogenic peptides results, not in the deposits visible by light microscopy, but rather from intracellular fibril aggregates and soluble oligomers that act as non-selective ion channels. Toxic IAPP fibrils and oligomers share a common structure with Alzheimer Disease (AD)-related [unreadable]-amyloid (A[unreadable]) fibrils and oligomers, suggesting a similar pathogenesis of type 2 diabetes mellitus (T2DM) and AD. Moreover, pancreatic [unreadable]-cells express high levels of AD-related peptides, and T2DM is frequently associated with AD. Non human primates (NHPs) represent ideal models to study the role of amyloidogenic peptides in [unreadable]-cell decompensation, because NHPs spontaneously develop islet amyloidosis and T2DM very similarly to humans. Our specific aims are: (1) to study [unreadable]-cell function, morphology, and ultrastructure in insulin sensitive (IS) and insulin resistant (IR) baboons;(2) to examine the effects of an acute increase in insulin secretory demand (achieved by partial pancreatectomy, PPx) on [unreadable]-cell function, morphology and ultrastructure (with particular emphasis on IAPP and A[unreadable]) in normal glucose tolerant (NGT) IS and IR baboons;(3) to examine the effects of different therapeutic interventions aimed at preventing PPx-induced [unreadable]-cell decompensation;(4) to test the hypothesis that abnormal A[unreadable] metabolism and glutamate transporter (GLT-1) activity may induce [unreadable]-cell death;(5) to study the molecular mechanisms responsible for IAPP- and A[unreadable]-induced cytotoxicity in vivo in the baboon pancreas (prior and after PPx) and in vitro in [unreadable]-cells lines and isolated baboon islets. Particular emphasis will be placed in amyloidogenesis, and endoplasmic reticulum (ER) stress, insulin signaling (insulin receptor substrate-2, IRS-2) and degradation (insulin degrading enzyme, IDE), and glutamate transport (GLT- 1) and metabolism (production of ?-aminobutyric acid, GABA);(6) to study the molecular mechanisms responsible for the beneficial effect of Exenatide on [unreadable]-cell expansion/neogenesis and survival in vivo and in vitro with particular emphasis on IAPP- and A[unreadable]-induced cytotoxicity and ER stress, insulin signaling and degradation, and glutamate transport and metabolism. Understanding the molecular mechanisms of amyloid deposition and [unreadable]-cell death in the baboon could provide the rationale for the novel therapeutic approaches. PUBLIC HEALTH RELEVANCE: Our project is aimed at: 1) Clarifying the physiological and molecular mechanisms of adaptation to increased metabolic demand of insulin-producing pancreatic cell in a novel non-human primate model of obesity and type 2 diabetes, the baboon, and the effect of new therapies aimed at the protection of insulin producing cells, 2) clarifying the cellular and molecular mechanisms underlying abnormal protein deposition and cell death in insulin-producing pancreatic in baboon islets of Langerhans and beta cell lines and the effect of new therapies aimed at preventing this phenomenon. Given the extremely high genetic similarity of this non human primate to humans and the possibility to dissect novel molecular mechanisms of insulin producing cell death as well as the mechanisms by which some drugs could prevent it, these studies will allow us to discover new treatments to prevent the loss of insulin-producing pancreatic cells in patients affected by type 2 diabetes mellitus.